The goal of this project is to elucidate the mechanisms that regulate the P family of transposable elements in Drosophila melanogaster. In the absence of regulation, the members of the P family actively transpose in the germ line, causing a syndrome of abnormalities called hybrid dysgenesis. The traits of this syndrome include an elevated mutation rate, frequent chromosome breakage, segregation distortion and sterility. When the P family is regulated, the incidence or severity of these traits is reduced. Genetic analyses have indicated that regulatory ability varies among Drosophila strains and that it depends on the P elements themselves. Strong and weak forms of regulation have been identified in natural populations. This project will test the hypotheses that regulation is mediated by P-encoded polypeptides and by antisense P RNAs. The first aim is to determine if different P-encoded polypeptides act synergistically to regulate P activity, the second aim is to determine if P-encoded polypeptides physically interact in vivo, the third aim is to see if naturally occurring P elements make antisense RNAs that contribute to the regulation of the P family, and the fourth aim is to see if strong P element regulation can be achieved by combining several weak repressor P elements. Transposable elements in general, and P elements in particular, are responsible for a high percentage of the mutations that occur spontaneously in Drosophila. It is important to elucidate the mechanisms that control the activity of these genomic parasites in order to understand the spontaneous mutation rate. In many species, including human beings, unregulated transposon activity would lead to an intolerable mutation load.